This section provides background information related to the present disclosure which is not necessarily prior art.
A multiplicity of infectious diseases in humans or animals are caused by viruses. Viruses do not have their own metabolism, which makes the causal treatment of viral infectious diseases difficult. In particular, they cannot be treated by antibiotics. Viricides that is, drugs that destroy viruses, are not currently available. Often a patient's immune system is not able to eradicate the infecting virus alone. Known substances with an antiviral action, so-called virustatics, prevent the spread or multiplication of viruses by various active mechanisms, which are connected with the infection cycle or multiplication cycle of the viruses. Known virustatics act in particular as DNA polymerase inhibitors. Known substances with nucleotide action are idoxuridine, aciclovir and ganciclovir and derivatives thereof. Other polymerase inhibitors are, for example, poscarnet and ribavirin.
Infections with the herpes simplex virus (HSV) are among the most common diseases in humans. More than 90% of the total world population are infected with this virus. Herpes simplex viruses (HSV) are divided into two closely related virus species (human herpes virus 1 (HSV1) and human herpes virus 2 (HSV2). The herpes viruses cause very different diseases of the herpes simplex, including herpes simplex encephalitis and neonatal herpes. The most widespread are herpes labialis and genital herpes.
A characteristic of HSV is persistence. After initial infection of the cells of the animal or human host organism, particularly of epithelial cells of the mucous membrane, the virus spreads into neuronal cells, in particular cells of sensory neurons, which innervate the primarily infected region. The viruses reach the ganglia via retrograde axonal transport and typically appear there in a latent state. The virus DNA persists, essentially unrecognized by the host's immune system, as a circular episome in the nucleus of the ganglia. During the latency phase, no virus replication takes place, the infected host is symptom-free. A reactivation of the latent viruses is triggered by stressors, such as a weakened immune system, exposure to sunlight, inflammatory events, hormonal or psychological effects (neuroendocrinological conditions) or nerve irritation. Virions thereby migrate axonally out of the ganglia back into the periphery and reinfect the tissue there, in particular the epithelial cells. The typical clinical picture of a herpes infection is shown by a lytic replication cycle in the epithelial tissue, and the tissue destruction resulting therefrom. The known therapy of a herpes infection is inadequate. Known virustatics can only relieve the symptoms and shorten the infection period but are not able to end the persistence of the viruses in the ganglia cells (eradication).
Many of the studies hitherto carried out on the latency mechanisms and reactivation analyses are obtained with the aid of mammalian cell lines. However, these test systems lack direct applicability to the in vivo situation in the patient. Consequently, animal experiments continue to be used in studies of the infection and latency mechanisms, but in particular in the development of active ingredients. It is desirable to develop in vitro test systems that permit a direct applicability of the results obtained thereby to the situation in the infected patient and that can replace animal studies.
With the aid of standardized three-dimensional in vitro skin equivalents, which are reconstituted from primary skin cells and/or skin cell lines, human skin can be reproducibly replicated. Physiologically such skin equivalents are largely comparable to native skin. As is known, they are used as in vitro tests systems for skin tissue (in vitro skin model).